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1.
Nat Immunol ; 22(1): 32-40, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33277638

RESUMEN

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.


Asunto(s)
COVID-19/inmunología , Inmunidad/inmunología , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Interferones/inmunología , SARS-CoV-2/inmunología , Antivirales/inmunología , Antivirales/metabolismo , COVID-19/genética , COVID-19/virología , Citocinas/genética , Citocinas/inmunología , Progresión de la Enfermedad , Expresión Génica/genética , Expresión Génica/inmunología , Perfilación de la Expresión Génica/métodos , Humanos , Inmunidad/genética , Inflamación/genética , Inflamación/inmunología , Gripe Humana/genética , Interferón Tipo I/genética , Interferones/genética , Tiempo de Internación , Pronóstico , SARS-CoV-2/fisiología , Carga Viral/genética , Carga Viral/inmunología , Interferón lambda
2.
Immunity ; 49(1): 120-133.e9, 2018 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-30005826

RESUMEN

B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention.


Asunto(s)
Antígenos CD/genética , Expresión Génica , Interleucina-10/biosíntesis , Células Plasmáticas/inmunología , Animales , Antígenos CD/inmunología , Subgrupos de Linfocitos B/inmunología , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Interleucina-10/genética , Activación de Linfocitos , Masculino , Ratones , Células Plasmáticas/fisiología , Receptores de Antígenos de Linfocitos B/metabolismo , Salmonelosis Animal/inmunología , Transducción de Señal , Linfocitos T/inmunología , Receptores Toll-Like/metabolismo , Regulación hacia Arriba/genética , Vacunas/inmunología , Proteína del Gen 3 de Activación de Linfocitos
3.
Immunity ; 44(5): 1114-26, 2016 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-27192577

RESUMEN

Regulatory T (Treg) cells expressing Foxp3 transcripton factor are essential for immune homeostasis. They arise in the thymus as a separate lineage from conventional CD4(+)Foxp3(-) T (Tconv) cells. Here, we show that the thymic development of Treg cells depends on the expression of their endogenous cognate self-antigen. The formation of these cells was impaired in mice lacking this self-antigen, while Tconv cell development was not negatively affected. Thymus-derived Treg cells were selected by self-antigens in a specific manner, while autoreactive Tconv cells were produced through degenerate recognition of distinct antigens. These distinct modes of development were associated with the expression of T cell receptor of higher functional avidity for self-antigen by Treg cells than Tconv cells, a difference subsequently essential for the control of autoimmunity. Our study documents how self-antigens define the repertoire of thymus-derived Treg cells to subsequently endow this cell type with the capacity to undermine autoimmune attack.


Asunto(s)
Antígeno CTLA-4/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Esclerosis Múltiple/inmunología , Glicoproteína Mielina-Oligodendrócito/metabolismo , Subgrupos de Linfocitos T/fisiología , Linfocitos T Reguladores/fisiología , Timo/inmunología , Animales , Autoantígenos/inmunología , Antígeno CTLA-4/genética , Células Cultivadas , Selección Clonal Mediada por Antígenos , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/genética , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/genética
4.
Eur J Immunol ; 53(2): e2250059, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36458588

RESUMEN

Toll-like receptors (TLR) control the activation of dendritic cells that prime CD4+ T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4+ T cell expansion. Addressing the underpinning mechanisms revealed that CD4+ T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen-specific CD4+ T cell expansion in lymph nodes, and the counter-regulatory role of TLR signaling in this process.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Ratones , Animales , Neutrófilos/patología , Receptor Toll-Like 9/metabolismo , Linfocitos T CD4-Positivos , Ganglios Linfáticos , Receptores Toll-Like/metabolismo , Ratones Endogámicos C57BL
5.
Immunity ; 42(3): 419-30, 2015 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-25786174

RESUMEN

Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.


Asunto(s)
Redes Reguladoras de Genes/inmunología , Inmunidad Innata , Macrófagos/metabolismo , Mitocondrias/metabolismo , Transcripción Genética/inmunología , Animales , Ácido Argininosuccínico/inmunología , Ácido Argininosuccínico/metabolismo , Aspartato Aminotransferasa Mitocondrial/genética , Aspartato Aminotransferasa Mitocondrial/inmunología , Ácido Aspártico/inmunología , Ácido Aspártico/metabolismo , Quimiocina CCL22/genética , Quimiocina CCL22/inmunología , Ciclo del Ácido Cítrico , Regulación de la Expresión Génica , Glutamina/deficiencia , Glicosilación , Interleucina-6/genética , Interleucina-6/inmunología , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/inmunología , Macrófagos/clasificación , Macrófagos/citología , Macrófagos/inmunología , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/inmunología , Ratones , Mitocondrias/genética , Mitocondrias/inmunología , Óxido Nítrico/inmunología , Óxido Nítrico/metabolismo , Transducción de Señal , Uridina Difosfato N-Acetilglucosamina/inmunología , Uridina Difosfato N-Acetilglucosamina/metabolismo
6.
Nature ; 556(7702): 501-504, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29670287

RESUMEN

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring 1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite 2 . Itaconate and its membrane-permeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines 2 , including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFE2L2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17-IκBζ-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI-IκBζ regulatory axis could be an important new strategy for the treatment of IL-17-IκBζ-mediated autoimmune diseases.


Asunto(s)
Factor de Transcripción Activador 3/metabolismo , Proteínas I-kappa B/metabolismo , Succinatos/metabolismo , Animales , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Estrés Fisiológico/efectos de los fármacos , Succinatos/administración & dosificación , Succinatos/química , Succinatos/farmacología , Succinatos/uso terapéutico , Receptores Toll-Like/inmunología
7.
Int J Mol Sci ; 24(16)2023 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-37629143

RESUMEN

We are reviewing the current state of knowledge on the virological and immunological correlates of long COVID, focusing on recent evidence for the possible association between the increasing number of SARS-CoV-2 reinfections and the parallel pandemic of long COVID. The severity of reinfections largely depends on the severity of the initial episode; in turn, this is determined both by a combination of genetic factors, particularly related to the innate immune response, and by the pathogenicity of the specific variant, especially its ability to infect and induce syncytia formation at the lower respiratory tract. The cumulative risk of long COVID as well as of various cardiac, pulmonary, or neurological complications increases proportionally to the number of SARS-CoV-2 infections, primarily in the elderly. Therefore, the number of long COVID cases is expected to remain high in the future. Reinfections apparently increase the likelihood of long COVID, but less so if they are mild or asymptomatic as in children and adolescents. Strategies to prevent SARS-CoV-2 reinfections are urgently needed, primarily among older adults who have a higher burden of comorbidities. Follow-up studies using an established case definition and precise diagnostic criteria of long COVID in people with or without reinfection may further elucidate the contribution of SARS-CoV-2 reinfections to the long COVID burden. Although accumulating evidence supports vaccination, both before and after the SARS-CoV-2 infection, as a preventive strategy to reduce the risk of long COVID, more robust comparative observational studies, including randomized trials, are needed to provide conclusive evidence of the effectiveness of vaccination in preventing or mitigating long COVID in all age groups. Thankfully, answers not only on the prevention, but also on treatment options and rates of recovery from long COVID are gradually starting to emerge.


Asunto(s)
COVID-19 , Síndrome Post Agudo de COVID-19 , Adolescente , Niño , Anciano , Humanos , SARS-CoV-2 , COVID-19/epidemiología , Reinfección , Pandemias
8.
Nature ; 507(7492): 366-370, 2014 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-24572363

RESUMEN

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Inmunidad/inmunología , Interleucinas/metabolismo , Infecciones por Salmonella/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos CD40/inmunología , Femenino , Humanos , Interleucina-10/metabolismo , Interleucinas/inmunología , Activación de Linfocitos , Macrófagos/citología , Macrófagos/inmunología , Masculino , Ratones , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Infecciones por Salmonella/microbiología , Linfocitos T/inmunología , Receptor Toll-Like 4/inmunología
9.
Immunity ; 33(5): 777-90, 2010 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-21093317

RESUMEN

The myeloid differentiation primary response gene 88 (Myd88) is critical for protection against pathogens. However, we demonstrate here that MyD88 expression in B cells inhibits resistance of mice to Salmonella typhimurium infection. Selective deficiency of Myd88 in B cells improved control of bacterial replication and prolonged survival of the infected mice. The B cell-mediated suppressive pathway was even more striking after secondary challenge. Upon vaccination, mice lacking Myd88 in B cells became completely resistant against this otherwise lethal infection, whereas control mice were only partially protected. Analysis of immune defenses revealed that MyD88 signaling in B cells suppressed three crucial arms of protective immunity: neutrophils, natural killer cells, and inflammatory T cells. We further show that interleukin-10 is an essential mediator of these inhibitory functions of B cells. Collectively, our data identify a role for MyD88 and B cells in regulation of cellular mechanisms of protective immunity during infection.


Asunto(s)
Linfocitos B/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Salmonelosis Animal/inmunología , Salmonella typhimurium/inmunología , Transducción de Señal/inmunología , Animales , Inmunidad Innata , Interleucina-10/inmunología , Células Asesinas Naturales/inmunología , Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/genética , Neutrófilos/inmunología , Vacunas contra la Salmonella/inmunología
11.
Eur J Immunol ; 44(5): 1251-7, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24615065

RESUMEN

B-cell depletion can improve disease in some patients with rheumatoid arthritis or multiple sclerosis, indicating the pathogenic contribution of B cells to autoimmunity. However, studies in mice have demonstrated that B cells have immunosuppressive functions as well, with IL-10 being a critical mediator of B-cell-mediated suppression. IL-10-secreting B cells have been shown to promote disease remission in some mouse models of autoimmune disorders. Human B cells also produce IL-10, and evidence is accumulating that human IL-10-producing B cells might inhibit immunity. There is considerable interest in identifying the phenotype of B cells providing IL-10 in a suppressive manner, which would facilitate the analysis of the molecular mechanisms controlling this B-cell property. Here, we review current knowledge on the B-cell subpopulations found to provide suppressive functions in mice, considering both the pathological context in which they were identified and the signals that control their induction. We discuss the phenotype of B cells that have IL-10-dependent regulatory activities in mice, which leads us to propose that antibody-secreting cells are, in some cases at least, the major source of B-cell-derived regulatory IL-10 in vivo. Anti-inflammatory cytokine production by antibody-secreting cells offers a novel mechanism for the coordination of innate and humoral immune responses.


Asunto(s)
Artritis Reumatoide/inmunología , Linfocitos B Reguladores/inmunología , Interleucina-10/metabolismo , Esclerosis Múltiple/inmunología , Células Plasmáticas/inmunología , Animales , Artritis Reumatoide/patología , Linfocitos B Reguladores/patología , Humanos , Inmunidad Humoral , Inmunidad Innata , Ratones , Esclerosis Múltiple/patología , Células Plasmáticas/patología
12.
Immunol Rev ; 233(1): 146-61, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20192998

RESUMEN

B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytokines, especially interleukin-10. Here, we review the stimulatory signals that induce interleukin-10 secretion and suppressive functions in B cells and the phenotype of the B cells with such characteristics. Finally, we formulate a model explaining how this process of immune regulation by activated B cells can confer advantageous properties to the immune system in its combat with pathogens. Altogether, this review proposes that B-cell-mediated regulation is a fundamental property of the immune system, with features of great interest for the development of new cell-based therapies for autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad , Linfocitos B/inmunología , Tolerancia Inmunológica , Activación de Linfocitos , Receptores Toll-Like/inmunología , Animales , Enfermedades Autoinmunes/terapia , Modelos Animales de Enfermedad , Humanos , Interleucina-10/inmunología , Ratones , Fenotipo , Transducción de Señal/inmunología
13.
Eur J Immunol ; 42(5): 1164-73, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22539290

RESUMEN

B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4(+) T-cell response, which was enhanced in B-cell-deficient mice. CD4(+) T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4(+) T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis.


Asunto(s)
Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Factores de Transcripción Forkhead/inmunología , Linfocitos T Reguladores/inmunología , Enfermedad Aguda , Traslado Adoptivo , Animales , Enfermedad Crónica , Activación de Linfocitos/inmunología , Depleción Linfocítica , Ratones , Índice de Severidad de la Enfermedad
14.
J Immunol ; 187(11): 5660-70, 2011 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-22058414

RESUMEN

TNF displays pathogenic activities in many autoimmune disorders. However, anti-TNF therapy in multiple sclerosis patients failed because of poorly understood reasons. We used a panel of gene-targeted mice that allowed cell-type specific ablation of TNF to uncover pathogenic and protective contributions of this cytokine during autoimmune disease of the CNS. T cells and myeloid cells were found to be critical cellular sources of TNF during experimental autoimmune encephalomyelitis (EAE). TNF produced by myeloid cells accelerated the onset of disease by regulation of chemokine expression in the CNS, driving the recruitment of inflammatory cells into the target organ. TNF produced by T cells exacerbated the damage to the CNS during EAE by regulating infiltration of inflammatory myeloid cells into the CNS. In secondary lymphoid organs, TNF expressed by myeloid cells and T cells acted in synergy to dampen IL-12p40 and IL-6 production by APCs, subsequently inhibiting the development of encephalitogenic T cell responses of Th1 and Th17 types. This dual role of TNF during EAE (protective in lymphoid organs and pathogenic in CNS) suggests that global TNF blockade might be inefficient in multiple sclerosis patients because augmented autoreactive T cell development in lymphoid tissues might overwhelm the beneficial effects resulting from TNF inhibition in the CNS.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Células Mieloides/metabolismo , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Separación Celular , Quimiocinas/biosíntesis , Quimiotaxis de Leucocito/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Células Mieloides/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Médula Espinal/inmunología , Médula Espinal/metabolismo , Médula Espinal/patología , Bazo/inmunología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/inmunología
15.
Eur J Immunol ; 41(6): 1696-708, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21469107

RESUMEN

Activated B cells can regulate immunity and have been envisaged as a potential cell-based therapy for treating autoimmune diseases. However, activated human B cells can also propagate immune responses, and the effects resulting from their infusion into patients cannot be predicted. This led us to consider resting B cells, which in contrast are poorly immunogenic, as an alternative cellular platform for the suppression of unwanted immunity. Here, we report that resting B cells can be directly engineered with lentiviral vectors to express antigens in a remarkably simple, rapid, and effective way. Notably, this neither required nor induced activation of the B cells. With this approach we were able to produce reprogrammed resting B cells that inhibited antigen-specific CD4(+) T cells, CD8(+) T cells, and B cells upon adoptive transfer in mice. Furthermore, resting B cells engineered to ectopically express myelin oligodendrocyte glycoprotein antigen protected recipient mice from severe disability and demyelination in EAE, and even induced complete remission from disease in mice lacking functional natural Tregs, which otherwise developed chronic paralysis. In conclusion, our study introduces reprogrammed quiescent B cells as a novel tool for suppressing undesirable immunity.


Asunto(s)
Linfocitos B/metabolismo , Tratamiento Basado en Trasplante de Células y Tejidos , Encefalomielitis Autoinmune Experimental/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Traslado Adoptivo , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos B/trasplante , Diferenciación Celular/genética , Células Cultivadas , Enfermedad Crónica , Anergia Clonal , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/fisiopatología , Encefalomielitis Autoinmune Experimental/terapia , Ingeniería Genética , Humanos , Terapia de Inmunosupresión , Interleucina-10/genética , Ratones , Ratones Noqueados , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/genética , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Asociada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Transgenes/genética
16.
Future Microbiol ; 16: 455-459, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33960807

RESUMEN

Tweetable abstract An opinion on the coronaviruses' evolution paradoxes, the continuing adaptation of the SARS-CoV-2 in humans following the zoonotic transmission, and clues into escape routes from host immune responses.


Asunto(s)
Evolución Molecular , Evasión Inmune , SARS-CoV-2/genética , COVID-19/inmunología , COVID-19/virología , Genoma Viral , Humanos
17.
Diagnostics (Basel) ; 12(1)2021 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-35054223

RESUMEN

BACKGROUND: Although several studies have been launched towards the prediction of risk factors for mortality and admission in the intensive care unit (ICU) in COVID-19, none of them focuses on the development of explainable AI models to define an ICU scoring index using dynamically associated biological markers. METHODS: We propose a multimodal approach which combines explainable AI models with dynamic modeling methods to shed light into the clinical features of COVID-19. Dynamic Bayesian networks were used to seek associations among cytokines across four time intervals after hospitalization. Explainable gradient boosting trees were trained to predict the risk for ICU admission and mortality towards the development of an ICU scoring index. RESULTS: Our results highlight LDH, IL-6, IL-8, Cr, number of monocytes, lymphocyte count, TNF as risk predictors for ICU admission and survival along with LDH, age, CRP, Cr, WBC, lymphocyte count for mortality in the ICU, with prediction accuracy 0.79 and 0.81, respectively. These risk factors were combined with dynamically associated biological markers to develop an ICU scoring index with accuracy 0.9. CONCLUSIONS: to our knowledge, this is the first multimodal and explainable AI model which quantifies the risk of intensive care with accuracy up to 0.9 across multiple timepoints.

18.
Adv Immunol ; 98: 1-38, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18772002

RESUMEN

B lymphocytes contribute to immunity in multiple ways, including production of antibodies, presentation of antigen to T cells, organogenesis of secondary lymphoid organs, and secretion of cytokines. Recent clinical trials have shown that depleting B cells can be highly beneficial for patients with autoimmune diseases, implicating B cells and antibodies as key drivers of pathology. However, it should be kept in mind that B cell responses and antibodies also have important regulatory roles in limiting autoimmune pathology. Here, we analyze clinical examples illustrating the potential of antibodies as treatment for immune-mediated disorders and discuss the underlying mechanisms. Furthermore, we examine the regulatory functions of activated B cells, their involvement in the termination of some experimental autoimmune diseases, and their use in cell-based therapy for such pathologies. These suppressive functions of B cells and antibodies do not only open new ways for harnessing autoimmune illnesses, but they also should be taken into account when designing new strategies for vaccination against microbes and tumors.


Asunto(s)
Anticuerpos/fisiología , Linfocitos B/fisiología , Inmunidad , Eritroblastosis Fetal/prevención & control , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Isoanticuerpos/uso terapéutico , Activación de Linfocitos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Globulina Inmune rho(D) , Linfocitos T/fisiología , Receptores Toll-Like/fisiología
19.
J Exp Med ; 215(4): 1035-1045, 2018 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-29511063

RESUMEN

Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1-/- mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1-/-, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.


Asunto(s)
Hidroliasas/metabolismo , Mycobacterium tuberculosis/inmunología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Tuberculosis/inmunología , Tuberculosis/metabolismo , Animales , Citocinas/inmunología , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Expresión Génica/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/microbiología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/inmunología , Especies Reactivas de Oxígeno/metabolismo , Succinatos/metabolismo , Transcripción Genética/inmunología , Tuberculosis/microbiología
20.
Cell Metab ; 24(1): 158-66, 2016 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-27374498

RESUMEN

Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1ß-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(-/-) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.


Asunto(s)
Inflamación/enzimología , Inflamación/patología , Macrófagos/metabolismo , Succinato Deshidrogenasa/antagonistas & inhibidores , Succinatos/farmacología , Animales , Respiración de la Célula/efectos de los fármacos , Femenino , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/patología , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/enzimología , Daño por Reperfusión/patología , Succinato Deshidrogenasa/metabolismo , Ácido Succínico/metabolismo
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